Adamantane compounds

ABSTRACT

WHEREIN EACH G independently represents hydrogen or straightchain alkyl of from one to six, both inclusive, carbon atoms; G&#39;&#39; represents hydrogen or acetyl; R represents hydrogen or alkyl of from one to six, both inclusive, carbon atoms; R&#39;&#39; represents halo, alkoxy containing from one to six both inclusive, carbon atoms in the alkyl group, hydrogen or alkyl of from one to six, both inclusive, carbon atoms; each R&#39;&#39;&#39;&#39; independently represents hydrogen or alkyl of from one to six, both inclusive, carbon atoms; each R&#39;&#39;&#39;&#39;&#39;&#39; independently represents hydrogen or alkyl of from one to six, both inclusive, carbon atoms or both R&#39;&#39;&#39;&#39;&#39;&#39; groups taken together represent oxo(-0); X represents halo; and each n independently represents an integer of from zero to one, both inclusive. The terms &#39;&#39;&#39;&#39;halo&#39;&#39;&#39;&#39; and &#39;&#39;&#39;&#39;halide&#39;&#39;&#39;&#39; are employed herein to designate occurrences of bromine, chlorine and iodine. The adamantane compounds of formula VII AND VIII are useful as agents to achieve a depressant action on the central nervous system of warm blooded animals. The adamantane compounds of formulas I, II, III, IV, V and VI are useful as intermediates in the synthesis of the compounds of formulas VII and VIII.   The present invention is directed to adamantane compounds of the formula:

United States Patent Szinai et al.

[ ADAMANTAN E COMPOUNDS [72] Inventors: Stephen S. Szinai, Wokingham; William H.

W. Lunn, Indianapolis, both of Ind.

[73] Assignee: Eli Lilly and Company, Indianapolis, Ind,

22 Filed: Apr. 27, 1970 [21] Appl. No; 32,406

Primary Examiner-Alex Mazel Assistant Examiner-Joseph A. Narcavage Attorney-Everet F. Smith, Kathleen R. Schmoyer and James L. Rowe [5 7] ABSTRACT The present invention is directed to adamantane compounds of the formula:

[ 51 June 6,1972

wherein each G independently represents hydrogen or straight-chain alkyl of from one to six, both inclusive, carbon atoms; G represents hydrogen or acetyl; R represents hydrogen or alkyl of from one to six, both inclusive, carbon atoms; R represents halo, alkoxy containing from one to six both inclusive, carbon atoms in the alkyl group, hydrogen or alkyl of from one to six, both inclusive, carbon atoms; each R" independently represents hydrogen or alkyl of from one to six, both inclusive, carbon atoms; each R' independently represents hydrogen or alkyl of from one to six, both inclusive, carbon atoms or both R' groups taken together represent 0xo(-0); X represents halo; and each n independently represents an integer of from zero to one, both inclusive. The terms halo and halide are employed herein to designate occurrences of bromine, chlorine and iodine.

The adamantane compounds of formula VII AND Vll I are useful as agents to achieve a depressant action on the central nervous system of warm blooded animals. The adamantane compounds of formulas I, II, III, IV, V and VI are useful as intermediates in the synthesis of the compounds of formulas VII and VIII.

2 Claims, No Drawings 1 2 ADAMANTANE COMPOUNDS amount of research has been carried out in an attempt to ob- CROSS REFERENCE o RELATED APPLICATIONS tain various derivatives of adamantane. While many derivatives have been rocured from adamantane, the are almost This application is a divisional application of our copending p y exclusively derivatives which are functionalized at the fix gz g f 2 med 1967 now 5 bridgehead positions or solely at the methylene positions.

BACKGROUND OF THE INVENTION Adamantane is a unique organic chemical having the fol- SUMMARY OF THE INVENTION lowing structure:

The present invention provides a uniqueapproach to 1,2- disubstituted adamantane compounds.

The subject matter of the present invention can more readily be understood by reference to the following summary reaction scheme. In this presentation, the symbol Ad" is used to designate a l-adamantyl radical, and the symbol to designate a divalent l,2-adamantylene radical.

PART A 0H As will be evident from this structural formula, the l, 3, 5, and Gram; 7 positions, the so-called bridgehead positions, are equivalent; 0 I and similarly, the 2, 4,639 and 10 positions, the so-called g methylene positions, are equivalent. Although adamantane- OH has been known for many years as a minor constituent of various petroleums, it was only around 1960 that methods became I AFCGPORaLOH available for its synthesis by ring closure of the bicyclo(3.3.l)n'onane system. Since then, a considerable Ad-CGz-COOH Ad-C Ora-43009.11: Ad-CGz-OHz-OH Ad-C Gn-C OX Part B CG2CR20H /OQ- i CU; AdCG -CR2OH Ad\ v Ad CR9 o A \C.()

X I k J X CGz-CHR-Nlllt Ad-CG;CHR-NHR Ad-CG;-CHRN Ad l l C3. Ad /CHR PART C The exact nature of complex obtained when boron m I trifluon'de is employed in the reaction of an alkanol and a dial- Q CGTCR 2-0 0 5 kyl malonate is not known. Generally, the following structure Ad CR2 Ag isassigned:

(lmlk DETAILED DESCRIPTION OF THE INVENTION 0 PARTA ulkO Part A of the present invention is concerned with the 0 synthesis of l-adamantaneethanol compounds serving as the immediate precursors for the cyclization reactions of Part B.

In a first embodiment, compounds offormula I;

and such structure is in conformity with the elemental analysis for such products, which analysis shows one mole of BF, (I) per mole of malonate. However, an alternate resonating struc- CH- C 0 0 40 ture is sometimes suggested: 1

wherein R is as hereinabove defined, are prepared by reacting l-adamantanol with a dialkyl malonate, to obtain the corresponding dialkyl l-adamantanemalonate (that compound of formula I wherein R represents alkyl), which is then hydrolyzed to obtain the corresponding free acid (that compound offormula I wherein R represents hydrogen). The com- 081k pounds of formula I are useful as materials from which to synthesize the compounds of formulas II and III.

Thus, it is believed that the following structure:

The above reaction of l-adamantanol and dialkyl malonate goes forward readily in the presence of a Lewis Acid catalyst, 4, and at temperatures of from 10 to 50 C., yielding the desired product and water as byproduct. Preferably, the reaction is conducted in an inert liquid reaction medium, such as an alkane, for example, hexane. Particularly good results are obtained when employing the reactants in substantially can be assigned to the boron complex obtained when boron equimolecular amounts.

trifluoride is employed in the present reaction of l-adamanl h t t t 2 Following completion of the reaction, the desired dialkyl ltanol and a dlalkyl malonme' a t ough the ahema e S we we adamantanemalonate can be separated from the reaction mixture as its boron difluoride complex, in which case the comulk plex is suspended in an inert hydrocarbon and distilled to drive 0 off the boron complexing portion, leaving the free dialkyl CIIZCH BF: ester which can be separated as such or hydrolyzed with base 0 to obtain the corresponding free acid. If the complex is not C isolated, the reaction mixture is subjected to hydrolysis conditions wherefrom the malonic acid is obtained directly by 7 methods well known to the art.

alkt

and (HX) n wherein the symbols G, R, R, X and n are as hereinabove defined, the free acid of formula I is decarboxylated to obtain l-adamantaneacetic acid, which can readily be converted to the corresponding acyl halide. To obtain those acyl halides wherein one or both G symbols stand for alkyl, the l-adamantaneacetic acid is esterified and then alkylated on the alpha position, and the resulting alkylated ester converted to the corresponding acyl halide by procedures which will be described hereinafter. All acyl halides, regardless of whether G is hydrogen or alkyl, are then further reacted to obtain those products wherein R represents hydrogen or alkyl, as defined.

The compounds of formula 11 wherein R is halo, alkyl, or alkoxy are useful as intermediates in the synthesis of the compounds of formula III; and the compounds of formula 11 wherein R is hydrogen or alkyl are useful as intermediates in the synthesis of compounds of formula IV wherein the n subscript of X (the substituent on the 2-position of the adamantane ring) is zero.

The above decarboxylation of the l-adamantanemalonic acid can be carried out by heating it to a temperature above its. thermal decomposition temperature, such as a temperature in the range of 190 to 250 C. The decarboxylation goes forward readily merely upon heating to the specified temperature range. Decarboxylation results in the desired l-adamantaneacetic acid with carbon dioxide as a byproduct. The ladamantaneacetic acid product is cooled to effect crystallization and can be purified by recrystal-lization from a suitable solvent.

Thereafter, l-adamantaneacetic acid is esterified, as by reaction with an excess amount of an alkanol in the presence of a mineral acid, for example sulfuric acid. The resulting ester can be alkylated to introduce one or two groups of the identity of G onto the alpha carbon atom. The alkylation comprises reacting the ester with an alkyl halide (GX) in the presence of a compound which converts the ester to its enolate form, for example, tn'tylsodium, sodium hydride, or sodium ethoxide. The reaction is carried out as described for method 299 of Wagner and Zook, Synthetic Organic Chemistry," (New York, N.Y.: Wiley and Sons, Inc., 1953), page 489 and references therein cited. This method is taught as giving only poor yields of alkylated product where, as here, the alpha carbon atom has two hydrogen atoms; these low yields are purportedly due to the tendency of such esters to undergo a competitive self-condensation reaction. However, the bulkiness of the adamantane ring severely limits such self-condensation; thus, both alpha hydrogen atoms can be replaced by this method, although yields on the second alkylation step will be lower. Furthermore, two different alkyl groups can be introduced by stepwise reaction with each of two different alkyl halide compounds.

The l-adamantaneacetic acid esters thus obtained:

the free acid compounds:

These free acid compounds or the corresponding esters are readily converted to the corresponding acetyl halide, such as by reaction with phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, or thionyl chloride, or, especially in the instance of the iodides, by halide exchange of an already obtained acyl halide, employing free HX as the reactant. In addition, the l-adamantane-acetic acid compounds can be converted to their corresponding alkyl esters, as by reaction with the alkanol of the desired alkyl ester group in the presence of a catalytic quantity of a mineral acid. These reactions are carried out in accordance with known procedures-- see Wagner and Zook, op. cit., especially chapters 14 and 17, and references therein cited.

The l-adamantaneacetyl halide compounds thus prepared are thereafter employed to prepare other compounds according to formula II wherein R represents hydrogen or alkyl. Those products wherein R represents hydrogen are readily prepared by the so-called Rosenmund reaction:

catalyst e.g., palladium [Wagner and Zook, op. cit., pages 159-160 and references therein cited and Kharasch et al., Grignard Reactions of Nonmetallic Substances (New York, N.Y.: Prentice-Hall Inc., 1954) Chapter VI] and thereafter oxidizing (Wagner and Zook, op, cit., pages 323-326 and references therein cited) to obtain the desired ketone:

alkyl Thus, in these procedures are prepared all of the compounds of the formula:

wherein R" is hydrogen or alkyl as defined. However, many of these compounds are also readily prepared by an alternate reaction scheme. In this alternate scheme, a l-adamantaneacetyl halide is reacted with diethyl malonate as its sodi- 1 heat ool-iLoan wherein R is hydrogen or C -C alkyl and G has the same meaning as hereinabove. The reaction is carried out in accordance with known procedures: see for example Walker et al., Journal of the American Chemical Society 68, (1946), page 1386.

However, regardless of the manner in which the compound of the formula,

wherein R" is hydrogen or alkyl as defined, is prepared, the compound can thereafter be subjected to reductive amination with a compound of the formula NH R in which R, as above defined, is hydrogen or alkyl of C -C by procedures well known in the prior art: see Wagner and Zook, op. cit., chapter 24, pages 662-664, and references therein cited, Houben-Weyl, op. cit., Band 11 Teil 1, page 602 and following, and N.G. Gaylord, Reduction with Complex Metal l-lydrides," (New York, N.Y.: lnterscience Publishers, 1956) page 322 and following.

The compounds resulting from the reductive amination:

wherein G and R have the same meaning as hereinabove, are useful as intermediates in the subsequent cyclization reactions of Part B to make the products of formulas V and VII, as well as the products of formula IV wherein the n subscript of X (at the 2 position of the adamantane ring) is one, which latter products are similarly useful in the subsequent cyclization reactions of Part B.

Subsequently, in a third embodiment, the l-adamantaneacetic acid, or corresponding ester or acyl halide compounds, are reduced to prepare the corresponding l-adamantaneethanol compounds, those compounds of formula III wherein each R" represents hydrogen and n represents zero.

wherein G is as defined hereinabove. These compounds, as well as all of the compounds of formula III wherein n represents zero, are useful as intermediates in the synthesis of the compounds of formula VI as well as those compounds of formula III wherein n represents one.

The precise reduction reaction employed to prepare the adamantaneethanol compounds is not critical. In a preferred reaction, a l-adamantaneacetic acid compound:

is reduced by reaction with lithium aluminum hydride in an inert liquid reaction medium. Suitable media include organic liquids, including ethers such as diethyl ether, tetrahydrofuran, and the dimethyl ether of diethylene glycol. The reaction mixture is preferably cooled below room temperature during initial contacting of the acid and lithium aluminum hydride. Thereafter, temperatures of 20 to 60 C. are acceptable and convenient. Particularly good results are obtained when employing the reactants in amounts representing three or more molecular proportions of lithium aluminum hydride for every two molecular proportions of the l-adamantaneacetic acid compound.

Those compounds of formula III wherein one or both R groups are other than hydrogen and wherein n is zero are also readily prepared. Where only one R is a group other than hydrogen, such compound is readily achieved as hereinabove discussed, by reaction of the corresponding l-adamantaneacetaldehyde with an appropriate alkyl magnesium ha- Iide:

Also, the same compound can be prepared by reduction of the corresponding ketone:

formula 11] wherein one R is a group other than hydrogen, and n is zero. Those compounds of formula III wherein both 9 10 R groups are other than hydrogen and n is zero are prepared X in a similar reaction of the compound of formula 1] wherein R ca o is alkyl, as defined, with an alkyl magnesium halide: l R

O OH (]3G2i )alkyl CGr--mlkyl 5 alkyl alkyl-MEX which rearrange to the corresponding 2-halo-l-adamantaneethanol or 2-halo-l-adamantaneethylamine:

([lGz-CR"2-OH (l3GaCHR-NlIli/ Thus, by these various procedures all the compounds of for- I mula lIl wherein n is zero can be prepared. Those compounds according to formula III wherein n is one are prepared and X utilized as described hereinbelow in Part B. v 1 and PART B Part B of the present invention is concerned with the The rearrangement is spontaneous in the instance when R" is cyclization of certain of the compounds prepared as described hydrogen, methyl or ethyl; when R represents an alkyl group hereinabove in Part A, these reactions yielding additional new larger than ethyl, the 2-halo-l-adamantaneethanol comcompounds of the following formulas: pounds and the 2-halo-l-adamantaneethylamine compounds ()G -CHR"-NHR can be rearranged by ultra-violet light. In either instance, the l resulting rearranged product is then readily dehydrohalogenated to yield the desired cyclic product of for- (Emu mulas VI or VII.

The reactions involved in this cyclization are summarized in the following reaction scheme:

. CGr-CG"z-OH CGrCR2"-0X l CGg-CHRN CGTCR Q l (L m RI! n. HOX HX CG2CHRNHR" OGPCHR"N/ (v1) and I 40 CGz-CHR (EX), CG2CRz-OH CGFCRZ CG 0=0 v11) As above defined, each G independently represents hydrogen or straight-chain alkyl of from one to six, both inclusive, car- HX bon atoms; each R" independently represents hydrogen or alkyl of from one to six, both inclusive, carbon atoms; each CGrCHELNHR" OGPOHR" R independently represents hydrogen or alkyl of from one to six, both inclusive, carbon atoms, or both R groups taken together represent oxo; X represents halo; and each n independently represents an integer of from 0 to 1, both inclusive. The compounds of formula VI are useful as intermediates in the s nthesis of the com ounds of fonnula VIII (Part C,

hereiribelow), and the com pounds of formula V are useful as wherem Z X have the Same meaning as hremabove intermediates in the synthesis of the compounds of formula In carrymg out the first Step of the above reacnon scheme VII. The utility of the compounds of formulas VII and VIII is the acyclic compound and the hypohalite are contacted com discussed in more detail hereinbelow veniently in an inert liquid reaction medium. Suitable as such In the first synthetic procedure, suitable for the preparation medla hjdlogenated hydrocarbons for example! carbon of all of the compounds of both formulas VI and VII, the corelaFmmdezdlchl9rmethanb l, f the like The responding acyclic compound ofone ofthe formulas precise form in which the hypohalite is supplied to the reaction mixture is not critical; however, preferred forms are (l) a solution, freshly prepared, of a hypohalous acid such as hypochloric or hypoiodic and (2) an alkali metal hypohalite, for example, sodium hypochlorite. The exact amounts of the reactants also employed are not critical, some of the desired product being obtained when employing any amounts. However, for good yields, it is necessary that the hypohalite be supis initially reacted in an aqueous medium with hypohalite, plied in excess, such as an amount representing from 1 to 10 which can be supplied as the acid or as a salt, preferably with 75 molecular proportions per molecular proportion of the startan alkaline earth or alkali metal. This reaction results in the ing l-adamantaneethanol or l-adamantaneethylamine compreparation of the corresponding -OX or -NX compound: pound. The reaction goes forward over a wide range of temand and

which in the instance of the latter type of compound, is readily separated from the reaction mixture by conventional procedures, typically by separation of the organic phase of the reaction mixture and removal of the reaction medium from this phase by evaporation. In the instance of the former type of product, many compounds cannot be separated, inasmuch as they undergo spontaneous rearrangement to the corresponding 2-halo-l-adamantaneethanol. This rearranged product, of course, can likewise be separated from the reaction mixture by conventional procedures.

In the instance of those compounds which do not spontaneously undergo rearrangement, as previously stated such rearrangement can be effected by exposing the compound to ultraviolet light, conveniently by exposing the original reaction mixture containing the compound to ultraviolet The exact intensity of the ultraviolet is not critical, some of the desired 2- halo-l-adamantaneethylamine being obtained even in the presence of a weak source of ultraviolet. Separation and, if desired, purification of the 2-halo compound, are carried out in conventional procedures.

After the Z-halo-l-adamantaneethanol or 2-halo-l-adamantaneethylamine is obtained, cyclization thereof is readily effected merely by heating at a temperature sufficiently high to drive off hydrogen halide, provision being made for its safe removal. Generally, temperatures of 200 to 280 C. give good results for the 2-halo-l-adamantaneethanol compounds, while with the 2-halo-l-adamantaneethylamines, temperatures of 170 C. to 250 C. generally give good results. Thus, in this manner are prepared all of the cyclic products of formulas VI and VII.

In addition, cyclic products of formula VI are readily prepared by another cyclization procedure. In this procedure, l-adamantaneethanol is reacted with either lead tetraacetate or mercuric acetate; either agent can be used alone or in conjunction with iodine, which enhances the rate of reaction.

wherein G and R have the same meaning as hereinabove. When excess lead tetraacetate is employed, there is preferentially prepared the corresponding compound of formula VI wherein the both R' groups taken together represent oxo.

In carrying out the above reaction, the reactants are contacted in an inert liquid reaction medium, for example, a hydrocarbon such as benzene; and the resulting reaction mixture is held for a period of time in the reaction temperature range, approximately C. to the boiling point of the particular hydrocarbon solvent. Separation and purification of the cyclized product are carried out in conventional procedures. Ultraviolet light can be used to enhance the rate of reaction.

The amine products of formulas IV, V and VII are readily obtained as either the free base or the corresponding hydrohalide salt. The salt is prepared by reacting the free base with a hydrogen halide; in many instances, it is preferred to separate the product as the hydrohalide salt. When desired, the salt can be converted back to the free base by neutralization.

PART C Part C of the present invention is concerned with derivatives obtained from the compounds of formula VI by cleavage of the furan ring:

(VIII) As above defined, each G independently represents hydrogen or straight-chain alkyl of from one to six, both inclusive, carbon atoms; each R' independently represents hydrogen or alkyl of from one to six, both inclusive, carbon atoms or both R groups taken together represent 0x0; and G represents hydrogen or acetyl. The compounds of formulas VII and VIII are useful as agents to achieve a depressant action on the central nervous system of warm blooded animals. The mode of administration is not critical; oral administration or administration by parenteral injection are suitable and preferred methods. Dosage rates vary with the particular compound and the particular species of animal; but generally, significant depression is obtained with the compounds of formula VIII at rates of or more milligrams/kilogram of animal body weight, by intraperitoneal injection, and at rates of 400 or more milligrams/kilogram of animal body weight, by oral administration. With the compounds of formula VII, significant depression is obtained at dosage rates of 25 or more milligrams/kilogram of animal body weight. The compounds are thus useful to calm warm blooded animals for easier handling. In use, the compounds are combined with standard inert pharmaceutical carriers to provide useful forms for administration, including tablets, capsules, solutions for injection, and the like.

In addition, the compounds of formulas VII and VIII are useful as antibacterial, amoebocidal and antitrichomonal agents. Good in vitro activity was found with aqueous formulations containing 500 micrograms or more per milliliter.

The derivatives of formula VIII are obtained by cleavage of starting materials of the formula:

wherein G and R' have the same meaning as hereinabove. Several methods of furan ring cleavage are known, and no precise method is critical to the preparation of the compounds of formula VIII. However, a convenient cleavage method for compounds where R' is hydrogen or alkyl is the reaction of the specified starting material with acetic anhydride in boron trifiuoride etherate. The reaction yields a diacetate; that is, product of formula VIII wherein G is acetyl. The diacetate is hydrolyzed to obtain the corresponding diol; that is, product of formula VIII wherein G is hydroxy. The cleavage reaction goes forward at temperatures over a wide range, but is most conveniently carried out at room temperature. Good results are obtained when employing the reactants in amounts representing an excess of the acetic anhydride, such as a 1- to 20-fold excess, and a catalytic amount of the etherate.

The resulting diacetate can be separated, and if desired, purified by conventional procedures. Alternatively, the reaction mixture containing the diacetate can be treated in situ with the hydrolysis agent to convert the diacetate to the corresponding diol, which is similarly separated, and if desired, purified by conventional procedures.

A convenient method for the preparation of those products of formula VIII wherein the R' groups are taken together and wherein G and R have the same meaning as hereinabove, is treated, as described hereinabove in Part B for the compounds of formula Ill, with lead tetraacetate or with mercuric acetate in the presence of iodine; or by simply heating the compound. The resulting product in the same cyclized product obtained from the compounds of formula III in accordance with Part B:

Therefore, cleavage and cyclization can be carried out repeatedly, as desired.

The following examples illustrate the present invention and will enable those skilled in the art to practice the same.

EXAMPLE 1 l-Adamantanemalonic Acid 15.1 parts of 1-adamantanol (0.11 mole) and 17.6 parts of diethyl malonate (0.11 mole) were stirred in 100 parts of nhexane at 5 C. while gaseous boron trifluoride was passed over the surface of the mixture. On saturation of the reaction mixture with boron trifluoride, as indicated by fumes emitting from the drying tube, boron trifluoride passage was stopped but stirring was continued at room temperature for 1.75 hours.

The mixture was then stirred in an ice-salt bath and sufficient 50 percent aqueous potassium hydroxide was added to neutralize the excess acid, the whole being maintained below C. throughout. Sixty parts of ethanol, 25 parts of water, and 20 parts of potassium hydroxide were then added and the bulk of the hexane was removed by distillation through a Vigreux column. The resulting mixture was refluxed for 20 hours. It was then allowed to cool to room temperature and extracted with ether. The ether extract was separated and washed with water. The resulting aqueous phase was stirred in an ice bath while 20 percent aqueous sulfuric acid was slowly added until the pH was below 1. Initially a fine precipitate containing inorganic material was deposited. At low pH, a coarser precipitate of the crude dicarboxylic acid precipitated and was collected by filtration. Recrystallization of the latter precipitate from a hexane-acetone solvent mixture afforded 14 parts of l-adamantanemalonic acid, m.p. l88-l92C.

(d). Analysis--Calc.: C, 65.52; H, 7.61. Found: C, 65.80; H, 7.58. 3

EXAMPLE 2 Diethyl l-Adamantanemalonate After a reaction between 15.1 parts of l-adamantanol and 17.6 parts of diethyl malonate with boron trifluoride had been carried out as described hereinabove in Example 1, the mixture was cooled in an ice bath while 75 parts of 99 percent ethanol were added with stirring. The temperature of the mixture was maintained below 5 C. while sufi'lcient 5 percent aqueous potassium hydroxide solution to make the mixture a1- kaline was added. The resulting mixture was rapidly extracted with ether, and the ether layer washed with ice-cold water and dried over magnesium sulfate. The ether was removed by distillation to afford oily crystals of a boron difluoride complex of diethyl l-adamantanemalonate. This complex was heated in boiling heptane, and the heptane was slowly distilled off through a Vigreux column until the distillate was nonacidic. Diethyl l-adamantanemalonatc was obtained from the residual oil by distillation under reduced pressure to afford a colorless oil boiling in the range; l28l31C./0.25 mm Mg. Elemental analysis was carried out: found for C, 69.54 (ca1., 69.39); found for H, 8.99 (ca.lc., 8.90).

EXAMPLE 3 l-Adamantaneacetic Acid 2.4 parts of l-adamantanemalonic acid were heated; after liquefaction occurred, the substance was further heated to 185 C. for 1 hour. On cooling, there was obtained a white crystalline mass, which was recrystallized from aqueous acetone to produce 1.3 parts of pure l-adamantaneacetic acid, melting at about C. Elemental analysis was carried out: Found for C, 74.01 (ca1c., 74.19); found for H, 9.39 (ca1., 9.34).

EXAMPLE 4 l-Adamantaneacetyl Chloride Sixty parts of l-adamantaneacetic acid and parts of thionyl chloride were heated together under reflux for 2 hours. Removal of the excess thionyl chloride by distillation at normal pressure and distillation of the residue at reduced pressure affor-ded 61 parts of l-adamantaneacetyl chloride, distilling in the range 84-8C./0.5 mm Hg.

EXAMPLE 5 l-Adamantaneethanol 2.5 parts of l-adamantaneacetic acid were dissolved in 50 parts of anhydrous diethylene glycol dimethyl ether and 2 parts of lithium aluminum hydride were added carefully to the solution with stirring and cooling. The resulting mixture was heated to 100 C. with stirring for 8-12 hours, and after cooling, poured slowly onto cracked ice. Acidification, extraction into ether, separation and washing of the organic phase with water, followed by removal of the solvent by distillation afforded the desired l-adamantaneethanol which was purified by crystallization to give 2 parts of pure product, melting at about 7374C.

EXAMPLE 6 l-Adamantaneethanol Twenty parts of l-adamantaneacetic acid were added in portions to a cooled suspension of 8 parts of lithium aluminum hydride in 400 parts of anhydrous diethylene glycol dimethyl ether. The reaction mixture was allowed to warm to room temperature, and thereafter stand overnight at room temperature. The excess lithium aluminum hydride was destroyed by the cautious addition of ethanol, and the resulting mixture poured on to cracked ice. Acidification, extraction into ether, separation and washing the organic phase with water, followed by removal of the solvent afforded l-adamant-aneethanol, which was purified by sublimation at reduced pressure to give 17.3 parts of pure product, melting at about 7678C.

Analysis: Calc. for C H O: C, 79.94; H, 11.18. Found: C, 79.67;l-1, 11.06.

EXAMPLE 7 2-Ch1oro- 1 -Adamantaneethanol C Hz CH2- 0 H Ten parts of l-adamantaneethanol were dissolved in 100 parts of carbon tetrachloride and the solution shaken vigorously during 10-15 minutes with three 150 milliliter portions of cold, freshly prepared, approximately 0.25 molar hypochlorous acid solution. After separation, the organic layer was washed with percent sodium bicarbonate solution, dried over anhydrous potassium carbonate, and allowed to stand at room temperature overnight. Removal of the solvent afforded l 1.0 parts of a pale yellow oil containing a number of components which were separated by chromatography on silica gel to give 15.8 parts of crude 2-chloro-l-adamantaneethanol.

EXAMPLE 8 l-Acetonyladamantane Diethyl ethoxymagnesiummalonate was prepared from diethyl malonate (68.6 g.), magnesium g.), and anhydrous ethanol (51 ml.) in ether (51 ml.). The mixture was stirred and maintained at a gentle reflux while a solution containing l-adamantaneacetyl chloride (80 g.) in dry ether (160 ml.) was slowly added. During the addition the reaction mixture became almost solid. When all the ethereal acid chloride had been added, the mixture was allowed to stand for 2 hours, and was then treated with dilute sulfuric acid and ether until the solid had all dissolved. The ether layer was separated, washed with water, and after removing the ether by distillation, the residue was boiled under reflux for 16 hours with a mixture containing glacial acetic acid (220 m1.), sulfuric acid (30 ml.) and water (100 ml.). After removing the bulk of the acetic acid by distillation in vacuum, the cooled solution was neutralized with 20 percent sodium hydroxide and extracted with ether. The ether extract was separated, washed with water and dryed over magnesium sulfate. The ether was removed by distillation to leave a colorless oil. Distillation of the oil at reduced pressure gave l-acetonyladamantane, 57.4 g. (79 percent of theory), distilling at about 7678C./0. l 5 mm Hg. Analysis for C l-l ozCalo, C, 81.19; H, 10.49. Found: C, 80.68; H, 10.76.

EXAMPLE 9 a,N-Dimethyll -Adamantaneethylamine CH CHa-CH-NH CH:

Five parts of l-acetonyladamantane, 97 parts of a 10 percent solution of methylamine in ethanol, and 10 parts of glacial acetic acid were boiled under reflux for 1 hour. After cooling, 0.25 parts of platinum oxide were added and the mixture hydrogenated at 60 psi for 4 hours at room temperature using a Parr apparatus. The catalyst was removed by filtration, the filtrate acidified with dilute acid, the ethanol removed therefrom by distillation, and the resulting aqueous residue extracted with ether. The aqueous phase was basified and again extracted with ether. Removal of the ether and distillation of the residue afforded 4 parts of the desired amine, a,N-

dimethyl-l-adamantaneethylamine, as a colorless oil; B.P.

82-84" C./0.55 mm Hg. Analysis: Calc. for C H N: C, 81.10; H, 12.15;N, 6.76. Found: C, 80.66; H, 11.91; N, 7.12.

EXAMPLE 10 N-Chloro-a,N-Dimethyll -Adamantaneethylamine IIN (flir- EXAMPLE 1 l 2-Chloro-a,N-Dimethyl- 1 -Adamantaneethylamine Hydrochloride 1 1.7 parts of N-chloro-a,N-dimethyll -adamantaneethylamine dissolved in 400 parts of 5N sulfuric acid in glacial acetic acid. The solution was irradiated, using a 1 liter photochemical reactor, for 1.5 hours, after which time a test sample gave no reaction for N-chloramine when treated with potassium iodide solution, thus showing that the reaction had proceeded to completion. The mixture was basified with 20 percent sodium hydroxide solution and extracted with ether. The ether extract was washed with water, dried over anhydrous magnesium sulfate, and the ether removed until the residual volume equalled approximately m1. Dry hydrogen chloride was passed into the solution, thus forming the hydrochloride salt of the amine which was recovered as a crystalline mass by filtration and was recrystallized from ether/ethanol to give 10.9 parts of 2-chloro-a,N-dimethyl-ladamantaneethylamine hydrochloride: M.P. 213C. Analysis--Calc. for C, H ,C1N-HCl: C, 60.43; H, 9.05; N, 5.03. Found: C, 60.25; H, 8.99; N,4.95.

EXAMPLE l2 Adamantano(2, 1 -b)tetrahydrofuran (JH?- C I12 l-Adamantaneethanol (0.9 g. 0.005 mole) and lead tetraacetate (2.9 g.; 0.065 mole) in benzene (35 ml.) were boiled under reflux, with stirring, for 3 hours. After cooling, the mixture was poured onto ice-water and extracted with ether. The ether layer was washed with water, dried over magnesium sulfate and the ether removed by distillation to leave an oil. Chromatography on silica gel (35 g.) in a 19:1 benzeneethyl acetate solvent mixture gave the pure cyclic ether, 0.78 g. Calculated for C H O: C, 80.84; H, 10.18. Found: C,

80.46; H, 9.89. The n.m.r. spectrum showed the presence of a doublet (l proton) at 6.651, confirming the cyclic nature of the product.

EXAMPLE 13 Adamantano( 2 l -b )tetrahydrofuran A sample of 2-chloro-l-adamantaneethanol, prepared as described in Example 7, was heated at 200C. in an atmosphere of nitrogen for 8 hours and the product chromatogl0 raphed on silica gel to give adamantano(2,l-b)tetrahydrofuran.

EXAMPLE l4 Adamantano( 2, 1 -b)tetrahydrofuran EXAMPLE l,2-Dimethyladamantano( 2, l -b)pyrrolidine CH2 CH-- 0 H3 2-Chlorol -[2-(methylamino)propyl]adamantane obtained from 18.4 grams of the hydrochloride thereof prepared as described in Example 11 was heated in an atmosphere of nitrogen at l85-95C. for .14 hours. Thereafter, the amine product was permitted to cool to room temperature, resulting in a somewhat gummy solid which was partitioned between ether and 2N hydrochloric acid. The aqueous phase was separated, made alkaline with 10 percent sodium hydroxide solution, and then extracted with ether. The ether layer was separated, washed with water, dried over magnesium sulfate, and the ether removed by distillation leaving an oily residue.

The oil was dissolved in 100 milliliters of acetic anhydride, and the resulting solution was kept at room temperature overnight and then refluxed for 2 hours. The acetic anhydride was removed in an evaporator. The residue was again partitioned between ether and 2N hydrochloric acid and the aqueous phase worked up as before to give a pale yellow oil, the desired 1,2-dimethyladamantano( 2, l-b)adamantane.

EXAMPLE 16 g l ,2-Dimethyladamantano(2,1-b)pyrrolidine Hydrochloride The free base, l,2-dimethyladamantano(2,1-b(pyrrolidine, prepared as described in Example 15, was dissolved in dry ether and dry hydrogen chloride passed into the solution causing precipitation of the corresponding hydrochloride salt, 1,2- dimethyladamantano(2,l-b)pyrrolidine hydrochloride. The precipitated salt was separated by filtration and, after recrystallization from ethanol-dioxan, melted at about 256 C. Analysis-calc. for C H N'HCI: C, 69.54; H, 10.01; N, 5.79. Found: C, 69.20; H, 10.35; N,- 6.16.

EXAMPLE l7 1 -Adamantaneacetyl Bromide Slightly over three molecular proportions of l-adamantaneacetic acid are reacted with one molecular proportion of 75 propyl-N-methyl-l-adamantaneethylamine phosphorus tribromide, to yield l-adamantaneacetyl bromide.

EXAMPLE 1 8 l-Adamantaneacetyl lodide Dry hydrogen iodide is passed into a solution of l-adamantaneacetyl chloride, prepared as described in Example 4, to obtain the corresponding l-adamantaneacetyl iodide.

EXAMPLE 19 l-Adamantanol and di-n-butyl malonate are reacted to yield di-n-butyl l-adamantanemalonate (m.w., 350.5).

EXAMPLE 20 l-Adamantanol and dimethyl malonate are reacted to yield dimethyl l-adamantanemalonate (m.w., 266.3).

EXAMPLE 21 l-Adamantanol and diisopropyl malonate are reacted to yield diisopropyl l-adamantanemalonate (m.w., 322.4).

EXAMPLE 22 1Adamantaneacetic acid and excess methanol are reacted together, in the presence of a minor amount of sulfuric acid, yielding methyl l-adamantaneacetate (m.w., 208.3).

EXAMPLE 23 l-Adamantaneacetic acid and excess isobutanol are reacted together in the presence of a minor amount of sulfuric acid, yielding isobutyl l-adamantaneacetate (m.w., 250.4).

EXAMPLE 24 l-Adamantaneacetyl chloride and gaseous hydrogen are reacted together in xylene, in the presence of a minor amount of palladium on barium sulfate, to yield l-adamantaneacetaldehyde (m.w., 178.3).

EXAMPLE 25 l-Adamantaneacetaldehyde and ammonia are reacted together, under the hydrogenation conditions of Example 24, yielding l-adamantaneethylamine (m.w., 179.3).

EXAMPLES 2627 l-Adamantaneethylamine and sodium hypochlorite are reacted together, yielding 2-chloro-l-adamantaneethylamine (m.w., 213.8) and upon heating, adamantano(2,l-b)pyrrolidine (m.w., 177.3).

EXAMPLES 28-30 l-Acetonyladamantane, prepared as described in Example 8, and sec-butylamine are reacted together, yielding N-secbutyl-a-methyl-l-adamantaneethylamine. Upon reaction with sodium hypoiodite, there is obtained 2-iodo-N-sec-butyl-amethyl-l-adamantaneethylamine (m.w., 375.3). Cyclization produces l-sec-butyl-2-methyladamantano( 2, l-b )pyrrolidine:

N-sec-butyl EXAMPLES 31-34 l-Adamantaneacetaldehyde and n-propylmagnesium bromide are reacted together, and the resulting product oxidized to yield l-(butyrylmethyl)adamantane(m.w., 220.4), which is converted by reductive amination with methylamine to am- (m.w., 235.4). This latter product is reacted with hypochlorous acid, yielding the corresponding 2-chloro-a-n-propyl-N-methyl-1-adamantaneethylamine, which upon heating cyclizes to l-methyl-2-npropyladamantano(2,1-b)pyrrolidine:

EXAMPLE 35 Diacetate of 2-l-lydroxy-l-adamantaneethanol A mixture of adamantano(2,l-b)tetrahydrofuran (1 1.3 g.), acetic anhydride (100 ml.) and boron trifluoride etherate (12.5 ml.) were mixed and permitted to stand at room temperature for two hours and then poured onto cracked ice (250 g.) and allowed to stand overnight. As a result of these operations, there was obtained, in solution, the diacetate of 2- hydroxy-l-adamantaneethanol.

EXAMPLE 36 Z-HYDROXY- 1 -ADAMANTANEETHA NOL The solution prepared as described in Example 35 and containing the diacetate of 2-hydroxy-l-adamantaneethanol was neutralized with 20 percent sodium hydroxide and extracted with ether. The organic phase was washed with water, dried over magnesium sulfate, and the ether removed by distillation to afford 2-hydroxy-l-adamantaneethanol as the diacetate, as an oil which was not further purified. The oil was taken up in ethanol (100 ml.). Potassium hydroxide (12 g.) was added, and the mixture boiled under reflux for 3 hours. Water (250 ml.) was added and the ethanol removed by distillation to give the 2-hydroxy-l-adamantaneethanol as a crystalline deposit which was recovered by filtration and dried to give 9.32 g. of product. Recrystallization from acetone/hexane afforded pure 2-hydroxy-l-adamantaneethanol, 8.02 g., m.p., 98100C. Analysis calc. for C, H O C, 73.43; H, 10.27. Found: C, 73.70; H, 10.33.

EXAMPLE 37 Adamantano( 2, l -b)tetrahydrofuran-2-one One part of 2-hydroxy-l-adamantaneethanol, 46 parts of lead tetraacetate and 50 parts of benzene were boiled under reflux for 3 hours. The mixture was allowed to cool and then poured into water. Ether was added and the organic phase was separated, washed with water, aqueous percent sodium bicarbonate solution, again with water, and then dried over magnesium sulfate. The ether was removed by distillation leaving an almost colorless oil containing several components. Chromatography of the oil on silica-gel yielded a fraction containing 0.35 parts of an oil which showed absorption in the infrared at 1,780 cm", indicating the desired adamantano(2,lb)tetrahydrofuran2-one product.

EXAMPLE 38 Z-Hydroxy- 1 -adamantaneacetic Acid Alkaline hydrolysis of the adamantano(2,1-b)tetrahydrofuran-2-one of the Example 37, and subsequent work up, yielded 2-hydroxy-l-adamantaneacetic acid. It was recrystallized from ethylacetate-n-hexane. The recrystallized substance melted at about l12.5-1 14 C.

EXAMPLE 39 Adamantano(2,1-b)tetrahydrofuran-2-one Sublimation of 2-hydroxy-l-adamantaneacetic acid in vacuo yielded adamantano(2,l-b)tetrahydrofuran-2-one as a waxy solid melting at about 8184 C.

The following additional examples are prepared in accordance with the foregoing examples and teachings:

In preferred embodiments, the present invention is directed EXAMPLES 481 Name Diacetate of B-n-butyl-fi-ethyl-Z-hydroxy-ladamantaneethanol fl-n-ButyI-fl-ethyl-2-hydroxy'ladamantaneethanol Diacetate of a,,B-dimethyl-2-hydroxy-ladamantaneethanol a,B-Dimethyl-2-hydroxy-l-adamantaneethanol Diacetate of a,a-di-n-hexyl-2-hydroxy-ladamantanecthanol una-Di-n-hexyl-Z-hydroxy-l-adamantaneethanol Diacetate ofa,a-dimcthyl-2-hydroxy-ladamantaneacetic acid a,a-Dimcthyl-2-hydroxy-l-adamantaneacetic acid a,a-Dimethyl-l-adarnantaneacetyl bromide Methyl a-n-hexyl-l-adamantaneacetate a-n-Butyl-a-methyl l -adamantaneacetaldehyde l-(n-Heptanoylmethyl)adamantane a,a,,B,B-Tetramethyl-l-adamantaneethanol ma,fi,B-Tetramethyl-Z-chlorol adamantaneethanol 2,2,3,S-Tetramethyladamantane(2,l-b)- tetrahydrofuran B-Ethyl-a-n-hexyll -adamantaneethanol fi-Ethyl-a-n-hexyl-Z-iodol -adamantaneethanol 3-Ethyl-2-n-hexyladamantano( 2,1-

b)tetrahydrofuran fi,/3-Dimethyl-N-chloro-ladamantaneethylamine B,fi-Dimethyl-2-chlorol -adamantaneethylamine a,N-Dimethyl-,B-n-hexyl-ladamantanecthylamine a,N-Dimethyl-fi-n-hexyl-N-bromo-ladamantaneethylamine 3-n-Butyl-2-ethyl-l-methyladamantano(2,l-

b)pyrrolidine 3-n-Propyladamantano(2, l -b)tetrahydrofuran 2-t-Butyl-1-methyladamantano(2,lb)pyrrolidine Di-n-hexyl l-adamantanemalonate a-n-l-lexyl-l-adamantaneacetyl chloride 2-Chloro-B-n-butyl-B-ethyl-ladamantaneethanol a,a-Di-n-hexyl-l-adamantaneethanol 2-lodo'a,/3-di-n-propyl-l-adamantaneethanol 3-n-Butyl-3-ethyladamantano(2,1-

b)tetrahydrofuran 2,2-Di-n-hexyladamantano( 2, l -b)tetrahydrofuran 2,3-Di-n-propyladamantano(2,I-bJtetrahydrofuran N,a,fi,B-Tetramethyl-l-adamantaneethylamine 2-Chloro-fi-ethyl-B-n-propyl-N-n-hexyl-1- adamantaneethylamine B-MethyLN-n-butyl-N-iodo-ladamantaneethylamine 1,2 ,3 ,3-Tetramethyladamantano( 2, 1 -b )pyrrolidine,

and its hydrochloride 1-nButyl-2-methyladamantano(2,l-b)pyrrolidine,

and its hydrobromide 3-Ethyl-3-n-propyl-1-n-hexyladamantano(2,l-

b)pyrrolidine, and its hydroiodide to subgenera as follows:

(Ila) Molecular Weight (IVa) (VIa) (VII) wherein M represents hydrogen or loweralkyl of from one to three, both inclusive, carbon atoms, the same moiety in each occurrence; M represents chloro, hydrogen, loweralkyl of from one to three, both inclusive, carbon atoms, or loweralkoxy of from one to three, both inclusive, carbon atoms; each M" independently represents hydrogen or loweralkyl of from one to three, both inclusive, carbon atoms; M' represents hydrogen or acetyl, the same moiety in each occurrence; X represents bromo, chloro, or iodo; and each n independently represents an integer of from 0 to 1, both inclusive.

The compounds of these preferred embodiments exhibit to an enhanced degree the properties generally exhibited by the present invention. In addition, they admit of ready synthesis, in accordance with the methods described hereinabove.

We claim 1. Compounds of the formula (IZGr-CHR wherein each G independently represents hydrogen or straight-chain alkyl of from one to six, both inclusive, carbon atoms; each R independently represents hydrogen or alkyl of from one to six, both inclusive, carbon atoms; X represents halo and each n independently represents an integer of from 0 to 1, both inclusive.

2. The compound of Claim 1 which is 1,2-dimethyl-adamantano( 2, l-b )pyrrolidine.

, rs STATES rArrNr UFFIQE P0-1b50 (5/69) v m v e 'rwmrr r lfihfi'll Patent No. 5, Dated June 6 1972 Inventor) Stephen S. Szinai and William H. W. Lunn' It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the heading, reference [72] should be changed to read as follows: --[72] Inventors: Stephen S. Szinai, Wokingham, England; William H. W, Lun n, Indianapolis, Indiana--; also in the heading, there, should be entries 52, 55, and 5h (specifying a claim for priority) as follows:

-- [32] Priority October a 1966 [55] Great Britain.

The word "formula" in the second line of reference [57] should read --fo rmulae--; also, in the first line of the last paragraph of reference ['57], "formula" should read --formulae-- and the word "AND" should be lower case.

In column 2, line 16, the word symbol "Ad should be inserted between the two quotation marks; also in column 2,

line 67, "Alk" should be -'-alk--.

In column 6, line 58, the letters "by" should be deleted after 289-290]"; also, in column 6, line 59, the word "of-- should be inserted before "formula II wherein. y

In column 7,.line about 16, "H should be -"Na--; also, in column 7, line about 50, "C -C should be "C -C In column 9, in the formula at about line &5, "HR"" should read --NR'-'-.-.

In column 10, line about 29, "CG" should be CR";- also in column 10, line about 553 HX" over the right-hand arrow should read '--h'y--; also in column 10, line about 5 "HR" in the right-hand, formula should read -'NR"--; also in column 10,

ng I r a 2 2 wires smrss mm assass- QER'WFECATE @F @QfiREQHQN Patent No. 5, 20 Dated June 6, 1972 e Stephen S. Szinai and William H. W. Lunn 2 It is certified that error appears in the above-identified patent and that said Letters'Patent are hereby corrected as shown below:

line 59, "wherein C,R", and X" should read -wherein G, R", and X--.

In column ll, line 58, "200 to 280 C." should read 20O'C. to 280C.- also in column .11, line 56', "CG C-0" of the right-hand formula should read -CG -C=0 In column l2, line about 11, "CG CH in the left-hand "formula should read CG -CR'" and "CG CH' "'-CG' in the right-hand formula should read --CG CR -0G' -'3 also in column 12; line about 15, "CG' in the right-hand formula should read --0G' In column 1 line 8, "Mg." should read --Hg.

In column 17, line 60, "(2,l-b(" should read (2,1-b)

In column 20, line 1, "EXAMPLES #81" should read --EX&MPLES hO- 8l--; also in column 20, line l l, "OZ-Ofidimethyl. should read fi-fidimethyl.- also in column 20, line 16, "Oz-a:- Dimethylr. should read B-B-Dimethyl. also 'in column 20, line about 25,, .adamantane. should read .adamantano.

Signed and sealed this 29th day of May 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attescing Officer Commissioner of Patents 

2. The compound of Claim 1 which is 1,2-dimethyl-adamantano(2,1-b)pyrrolidine. 